The differentiation of osteoclasts (OCs) is dependent upon critical signals provided by two molecules: osteoprotegerin (OPGL) and macrophage colony stimulating factor (M-CSF). The binding of M-CSF to its receptor (c-fms) results in phosphorylation of tyrosine residues in the cytoplasmic portion of the receptor, generating downstream signals. Although structure-function analyses of c-fms have been carried out previously in other cell types, these studies have yielded conflicting results. In addition, there is question whether results obtained with other cell types can be extrapolated to c-fms signaling in OCs. This proposal will therefore determine the tyrosine residues critical for osteoclast (OC) survival, proliferation and differentiation of OC precursors, and the function of mature OCs.